Systemic lupus erythematosus (SLE) is a severe autoimmune disease that can affect multiple organs throughout the body. Unfortunately, the currently available drugs are not effective for all patients, and the drugs can have significant side effects. The complement system is integrally involved with several aspects of SLE. The classical pathway protects against the development of SLE. On the other hand, evidence suggests that C3d covalently bound to antigens lowers the threshold for developing autoimmunity through its interaction with complement receptor 2 (CR2). Complement activation is also a critical downstream mediator of target organ injury in SLE. We developed a monoclonal antibody, designated mAb 3d8b, that binds C3d and blocks autoantigen complex from ligating CR2. Furthermore, mAb 3d8b targets sites of complement activation and C3d fixation in vivo. We generated unique chimeric proteins that link 3d8b to molecules that inhibit the complement effector functions. These chimeric molecules are able to block the two key pathologic roles of complement in the development of SLE: they prevent the development of high affinity autoantibodies, and they inhibit pro-inflammatory complement activation in target organs. Because the drugs do not block the classical pathway, however, they do not interfere with complement's protective effects. Furthermore, the risk of infection with tissue-targeted drugs is expected to be less than with untargeted complement inhibitors. Based on these considerations, the overall hypothesis of this project is that the 3d8b-targeted complement inhibitors will be more protective in a model of SLE than untargeted complement inhibitors, through both modulation of autoantibody production and inhibition of the downstream pro-inflammatory effects. To test this hypothesis, the following specific aims will be pursued. Aim 1) Examine the effects of C3d-targeted complement inhibitors on autoimmunity in the (NZBxNZW)F1 model of lupus. We will determine the pharmacokinetics and pharmacodynamics of the targeted drugs compared to untargeted complement inhibitors, and we will test the effects of these drugs on systemic autoimmunity. Aim 2) Compare the efficacy of single and combined therapeutic complement inhibitors for treating kidney disease in the (NZBxNZW)F1 model of lupus. In this aim we will test the efficacy of the different strategies for preventing the pathologic effects of complement in lupus nephritis. Aim 3) Characterize the systemic immunomodulatory effects of single and combined therapeutic complement inhibitors. In this aim we will examine the effects of the targeted and untargeted complement inhibitors on myeloid and lymphoid cell populations from spleen, peripheral blood, and bone marrow of (NZBxNZW)F1 mice. The studies in this proposal are innovative, because they test novel molecules designed to block multiple mechanisms of autoimmunity and tissue injury in SLE. This project is significant, because it develops a new class of drugs that may improve outcomes in SLE while reducing treatment side effects.